The Lipase Inhibitor Orlistat

Many clinical trials have been performed on orlistat during the last few years and one formulation of the drug (Xenical ) was Ucensed in the European Union in 1998 (Brooks, 1998) and in the United States in 1999. The results of clinical studies have indicated that Xenical reduces fat absorption up to 30% (Zhi et al., 

1994) during a meal. Xenical has dose-dependent effects up to 400 mg per day and a plateau is then observed (Zhi et al., 1994). When Xenical is administered in therapeutic doses (120 mg wifh the main meals) in conjunction wifh a mildly hypocaloric diet, obese patients have lost around 10% of fheir bodyweight over a 1 year period (Sjostrom et al., 1998). 

Design of Clinical Studies for Quantification of Lipase and Lipolysis Inhibition 

Some HGL inactivation was observed in the control experiments (29.4% with the liquid meal 12.3% with the solid meal Tab. 10.4). Partial inactivation of HGL was found to occur mostly in the samples with the lowest pH values (1-2), which were collected at the end of the meal gastric emptying process. 

Meal Treatment Amounts of HCL secreted (mg) Active HCL HCL inhibition r 6) 

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Panels A and C show the pyloric output of lipolysis products in the absence and in the presence of the lipase inhibitor orlistat, respectively. Panels B and D show the duodenal output at the Angle of Treitz of lipolysis products in the absence and in the presence of the lipase inhibitor orlistat, respectively. 

Weber C, Tam YK, Schmidtke-Schrezenmeier G, Jonkmann JHG, vanBrummelenP. Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antih3 rtensive drugs in healthy volunteers. EurJ Clin Pharmacol (1996) 51, 87-90. 

Lipase Inhibitor Orlistat (Xenical, Roche) is prescribed for the treatment of obesity. It inhibits the gastrointestinal lipase enzymes by binding to the lipase through the serine site and inactivates the enzyme. Fat in the form of triglycerides cannot be hydrolyzed by the lipase and converted to free fatty acids and monoglycerides. Thus, there is no uptake of fat molecules into the cell tissue. 

Tonstad S, Pometta D, Erkelens DW, Ose L, Moccetti T, Schouten JA, Golay A, Reitsma J, Del Bufalo A, Pasotti E et al. (1994) The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia. Eur J Clin Pharmacol 46 4f)5—410... 

The side effects of orlistat are extremely unpleasant. Patients may experience abdominal pain, gas, and discomfort when taking this drug the abdominal problems that occur are even more intense after the patient eats a high-fat meal. Since orlistat is a lipase inhibitor, it prevents fat from being absorbed by the body. Thus, the fat in food comes out of the body in the stool, causing these side effects ... 

Enantioselective hydrogenation of />-kelo esters catalyzed by the modified Raney Ni is useful for the synthesis of biologically active compounds, as shown in Figure 32.15 [56-58]. A large-scale synthesis of (-)-tetrahydroHpstatin (orlistat), a pancreatic lipase inhibitor (F. Hoffmann-La Roche AG), is carried out using this method [58]. 

The active ingredient of Xenical, orlistat, is a pancreatic lipase inhibitor. Side-effects include faecal urgency, liquid oily stools and flatulence. Xenical capsules are administered before, during or up to 1 hour after the two main meals, twice daily. 

Orlistat is a pancreatic lipase inhibitor used in conjunction with a hypocaloric diet to reduce the absorption of dietary fat in obese patients. Orlistat is administered twice daily immediately before, during or up to 1 hour after each meal. If the meal contains no fat there is no need to take Orlistat. 

Pharmacology Orlistat is a reversible lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. It exerts its therapeutic activity in the lumen of the stomach and small intestine. 

Another type of diet pill received FDA approval in 1999. Orlistat, sold under the name of Xenical, was a lipase inhibitor. It affects the body s lipase enzyme and blocks about 30% of fat absorbed by the body. 

Orlistat is a gastrointestinal lipase inhibitor that blocks fat absorbtion in the intestine. 

Heck AM, Yanovski JA, Calis KA (2000) Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy 20 270-279... 

Orlistat (Xenical /Roche) is a reversible gastric and pancreatic lipase inhibitor. The compound has no effect on appetite suppression but rather acts by inhibiting dietary fat absorption from the GI tract. Sibutramine (Meridia /Abbott) and its major active metabolites are re-uptake... 

Regrettably, the pharmacologist must confess that no drugs exist that can be recommended for the purpose of weight reduction. The so-called appetite suppressants (anorexiants) act only, if at all, for a limited period and are fraught with side effects. Most anorexiants are derivatives of metham-phetamine that have been withdrawn from the market. A different mechanism of action is involved in the case of an inhibitor of pancreatic lipase, which is required in the intestines for fat absorption. This inhibitor (orlistat) diminishes fat absorption so that fats reach the lower bowel, where they can cause disturbances flatulence, steatorrhea, and frequent need to relieve the bowels occur in about 30% of affected subjects. These symptoms correspond exactly to those seen in pancreatic hypofunction which are then usually treated with pancreatic lipase. Before an obese person submits to treatment with orlistat, he or she should voluntarily reduce the food fat content by one half to live free of such unpleasant adverse effects. 

In Fig. 9.4 are depicted the chemical structures of all inhibitors we will discuss diethyl p-nitrophenyl phosphate (Egoo), orlistat and O-mefhyl-O-(p-nitrophenyl) n-undecylphosphonate (Cll-P). In order to study the effects of these reagents, which can in principle modify covalently several essential amino acid residues of the lipases, we have proposed four different methods [50-52], depending upon the order of addition of lipase, substrate and inhibitor (Fig. 9.5). 

Studies of the partitioning of orlistat between the micellar and oil phases were performed at our laboratory [52, 110]. Even in the presence of bile salts, orlistat was found to be mostly associated with the oil phase. This interesting physicochemical property is probably a requirement for prototypic lipase inhibitors to be effective under physiological conditions, i.e. in the presence of bile and dietary lipids. 

In the lipase assay system, when the (E, THLc, E-THLoj and E-THL02) mixture was added to a TAG emulsion, the weakef complex (E-THLoj) was hydrolyzed, explaining the reactivation process as revealed by the existence of lag times. The hydrolysis of this weak complex was enhanced when bile salts were present in the assay medium, probably due to the formation of a mixed orlistat/lipase/bile salt complex. The fact that the reactivation of HPL did not reach 100% of its initial value (before incubation with THL) at the end of the kinetic experiments (Fig. 9.13) might be attributable to the existence of a second fraction of lipase molecules, which is covalently and irreversibly inhibited by orlistat (E-THL02). The coexistence of two different forms of orlistat covalently bound to HPL may be due to the inhibitor molecule being differently oriented in the catalytic cavity of the lipase molecule. The existence in the catalytic cleft of lipases of two different orientations in the case of molecules of substrate analogues was previously reported [113, 114]. 

It is seems clear that further chemical, biochemical and physiological studies of lipase inhibitors will improve our knowledge of this important and interesting family of carboxylester hydrolases. Orlistat was the first lipase inhibitor to be launched on the market. It is to be expected that other molecules will be developed as beneficial drugs for human health. 

Orlistat, a GI lipase inhibitor used for weight loss, was administered over a 4-year period that resulted in a 37% reduction in the progression of type 2 diabetes mellitus in a group of insulin-resistant obese patients. Finally, although... 

The client is prescribed orlistat (Xenical), a lipase inhibitor. Which statement by the client indicates the client requires more teaching ... 

Zhi J, Moore R, Kanitra L, Mulligan TE. Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers. J Clin Pharmacol (2003) 43, 428-35. 

Orlistat (tetrahydrolipstatin) is a reversible inhibitor of oral, gastric, and pancreatic lipases. This inhibitor forms an ester linkage with serine (serine-152) in the active site of the lipase so that a decrease in the rate of lipid hydrolysis will occur [37]. Orlistat decreases the oral taste sensitivity to both oleic acid and triolein in obese subjects [38]. These results further suggest a role for lingual lipase in oral fat hydrolysis and detection. However, a conclusive role for human lingual lipase in oral fatty acid hydrolysis and detection still remains imclear at the present time [39]. 

Orlistat (Fig. 20.7) is the only Gl tract dmg indicated in the BNF, and is a lipase inhibitor, which reduces fat intake. This dmg is a synthetic analogue of lipstatin which is a namrally occurring substance produced by Streptomy-ces toxytricini. Orlistat is an iueversible inhibitor of pancreatic and gastric lipases and as such it prevents these lipases from breaking down triglycerides into their absorbable form (free fatty acids and monoglycerols). The triglycerides are thus eliminated without absorption and thus there is a decreased dietary intake of fat. 

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